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Newly Discovered Neural Mechanism of Social Isolation

By Nicole Xu

Social isolation is by no means a new phenomenon, but the issue is currently being highlighted as lockdown and social distancing measures during the COVID-19 pandemic have severely dwindled person-to-person interaction. People of all ages struggle with social isolation, but it can have especially detrimental and long lasting effects in developing children.

Previous research has shown that social isolation of developing children has significant downstream effects on adult sociability and brain function, but the exact biological mechanism was unclear. Researchers at Icahn School of Medicine at Mount Sinai have clarified this mechanism through studying the brains of adult mice that were subject to social isolation in their juvenile years right after weaning.  It has been previously shown that the medial prefrontal cortex (mPFC) of the brain regulates social interaction in humans and mice and that neurons stemming from the mPFC are less excitable when mice experience juvenile social isolation. However, the target of these neurons was unknown until now. 

First, researchers identified that some neurons from the mPFC target the posterior region of the paraventricular nucleus of the thalamus (pPVT) through fluorescent imaging. They then wanted to clarify the role of these mPFC→pPVT neurons in social interaction, so they measured the activity of these neurons under various conditions. Mice that were housed in a group during their juvenile years were compared to mice that experienced juvenile social isolation. They found that mice subject to juvenile social isolation had near baseline levels of mPFC→pPVT neuron activation when exposed to another mouse whereas the group-housed mice had high levels of activation compared to baseline. This shows that social interaction at the juvenile stage is necessary for the brain circuit to function properly during adult socialization. 

To identify the exact mechanisms that contribute to the lower neural activation in socially isolated mice, researchers studied the electrical currents generated by neurons. There are two different types of currents: inhibitory and excitatory, and the ratio of excitatory to inhibitory currents (E/I ratio) indicates overall excitability of the neurons. In the mice that were socially isolated in their juvenile years, there was a decrease in intrinsic excitability of the mPFC→pPVT neurons in addition to an increased presence of inhibitory currents. This results in an overall decrease in the E/I ratio, meaning less neural excitability. Other mPFC neurons did not show these characteristics, suggesting that the effect of juvenile social isolation is fairly specific to mPFC→pPVT neurons. 

Artificial activation of mPFC—>pPVT neurons could rescue decreased sociability in mice that were previously socially isolated. Additionally, the activation of these neurons did not create any unintended side effects like anxiety or heightened motor activity. 

The importance of childhood development is highlighted in this study as the social environment during juvenile years shapes adulthood interactions. Since social abnormalities in these mice were observed in adulthood as opposed to directly after juvenile social isolation, learned behavior for social interaction might be fixed after childhood, leading people to be unable to adapt to socializing if not exposed properly earlier in life. This means that prevention of social isolation should be especially highlighted during childhood. Additionally, clarification of the role of mPFC→pPVT neurons in social behavior creates a new potential treatment target for various diseases and conditions that may present with social deficits. 

Identifying targets in social behavior to treat social deficits has been an ongoing effort for quite some time, especially for disorders like autism. One of the key markers of autism is a deficit in social communication yet currently, there are no FDA approved drugs to treat it. Behavioral therapy is the standard treatment to try to improve social communication skills in people with autism, requiring continuous years of meetings starting from childhood to be effective. This commitment to consistent treatment is difficult since behavioral therapy is not always covered by insurance and can be difficult to access. Furthermore, even if therapy is fully effective, it only treats the symptoms of autism and not the actual biological cause. 

As more targets like the mPFC-> pPVT neuron are discovered in regards to social behavior, the possibility of directly treating the pathology of diseases that present with social deficits increases. Hopefully this decreases the long term detrimental effects of social isolation and other diseases and disorders. 

References

Yamamuro, K., Bicks, L.K., Leventhal, M.B. et al. A prefrontal–paraventricular thalamus circuit requires juvenile social experience to regulate adult sociability in mice. Nat Neurosci 23, 1240–1252 (2020). https://doi.org/10.1038/s41593-020-0695-6

Frye, Richard E. “Social Skills Deficits in Autism Spectrum Disorder: Potential Biological Origins and Progress in Developing Therapeutic Agents.” CNS Drugs, Springer International Publishing, Aug. 2018, www.ncbi.nlm.nih.gov/pmc/articles/PMC6105175/. 

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